Wifling, David and Pfleger, Christopher and Kaindl, Jonas and Ibrahim, Passainte and Kling, Ralf C. and Buschauert, Armin and Gohlke, Holger and Clark, Timothy (2019) Basal Histamine H-4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif. CHEMISTRY-A EUROPEAN JOURNAL, 25 (64). pp. 14613-14624. ISSN 0947-6539, 1521-3765
Full text not available from this repository. (Request a copy)Abstract
Histamine H-4 receptor (H4R) orthologues are G-protein-coupled receptors (GPCRs) that exhibit species-dependent basal activity. In contrast to the basally inactive mouse H4R (mH(4)R), human H4R (hH(4)R) shows a high degree of basal activity. We have performed long-timescale molecular dynamics simulations and rigidity analyses on wild-type hH(4)R, the experimentally characterized hH(4)R variants S179M, F169V, F169V+S179M, F168A, and on mH(4)R to investigate the molecular nature of the differential basal activity. H4R variant-dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F169(45.55) dips into the orthosteric binding pocket only in the case of hH(4)R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H4R activation that are of importance for other GPCRs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTORS; RESOLUTION CRYSTAL-STRUCTURE; CONSTITUTIVE ACTIVITY; BETA(2)-ADRENERGIC RECEPTOR; ADRENERGIC-RECEPTOR; ALLOSTERIC MODULATION; MOLECULAR-DYNAMICS; ACID RESIDUE-79; IONIC LOCK; RIGIDITY; basal activation; computational chemistry; GPCR; molecular dynamics; rigidity analysis |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Mar 2020 05:06 |
| Last Modified: | 06 Apr 2020 06:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25999 |
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